Physiology of LGR7 and LGR8 in Gonadal Tissues

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DESCRIPTION (provided by applicant): The classic hormone relaxin belongs to a family of peptide hormones with a conserved two-chain structure. Extensive studies have demonstrated that relaxin plays important roles in female physiology during pregnant and nonpregnant states and a paralogous gene, INSL3, is important in male reproductive development. Although relaxin is produced by ovarian luteal cells whereas INSL3 is produced by testis Leydig cells as well as ovarian the cal and luteal cells, their physiological roles in the gonads are unclear. Earlier studies suggested the presence of relaxin and INSL3 binding sites in target tissues including the gonads. However, studies on the putative receptors for these ligands were limited due to difficulties involved in performing ligand-binding assays for these proteins expressed at low levels. Our recent studies demonstrated that relaxin activates the orphan receptors LGR7 and LGR8 whereas INSL3 specifically activates LGR8. In addition to demonstrating the role of cAMP pathways in LGR7 and LGR8 signaling, we generated the soluble ligand-binding ectodomain of LGR7 to serve as a functional antagonist. Treatment with the soluble ectodomain of LGR7 delayed parturition of pregnant mice. Here, we propose to analyze the domains of LGR7 and LGR8 that are important for receptor function by testing ligand signaling of chimeric receptors. Based on our findings of LGR8 variants in cryptorchid patients, we will further test INSL3 activation of a LGR8 variant. We have obtained preliminary data indicating the expression of LGR7 and LGR8 in the testis and ovary and propose to elucidate the physiological roles of LGR7 and LGR8 in gonadal physiology. We will characterize the expression of LGR7 and LGR8 in specific gonadal cell types and their responsiveness to relaxin and INSL3 based on cAMP production and other responses. We will use the soluble ectodomains of LGR7 and LGR8 as functional antagonists to demonstrate the physiological roles of relaxin and INSL3 in testis and ovarian physiology in vivo. The proposed studies should provide a better understanding on the role of relaxin-related hormones and LGR7 and LGR8 receptors in gonadal physiology and other reproductive processes.